AR inhibitor treatment selection in nmCRPC


Considerations that factor into which androgen receptor inhibitor is selected as treatment for nonmetastatic castration-resistant prostate cancer.

Benjamin H. Lowentritt, MD, FACS: I didn’t know if you wanted to mention this. An interesting thing is that the nmCRPC [nonmetastatic castration-resistant prostate cancer] indications came out a little earlier in 2018, so we have a little longer-term follow-up and more of the secondary publications on things like quality of life and patient-reported outcomes. To my earlier questions, they’re pretty similar. However, there was a third entry in that space, which was with darolutamide. Do you want to talk about the difference with darolutamide and some of the data surrounding it?

Julie N. Graff, MD: Thanks, Ben. Yes. As you said earlier, you can’t really compare trial to trial. It’s not kosher, but we still do it. I was talking to a colleague about a specific study, and I said, “Not only can we not compare across these trials, if we did the exact same study today, we’d probably have a different result.” Maybe it’s miniscule, maybe it’s major. Some of the beauties of darolutamide are that it doesn’t seem to cross the blood-brain barrier, and in the trial that got it approved for nonmetastatic CRPC [castration-resistant prostate cancer], they included patients at risk of seizure and even those with intracranial issues like a mass. That’s very important. It’s very nice to have that in our armamentarium, because there are always going to be some patients—even though they’re rare—who have a history of seizures, and we can use that drug.

On the other side of things, it looks like it might be better tolerated, as you’re saying. It looks like people don’t have as many falls and people aren’t quite as fatigued. When you think about enzalutamide in the phase 1 studies, fatigue was one of the major dose-limiting features. Patients sometimes get so fatigued that they can’t drive their car. That’s unusual, but it can be profound. It’s possible that darolutamide is better tolerated. We at OHSU [Oregon Health & Science University] and others are doing a clinical trial looking at head-to-head darolutamide and enzalutamide to try to more definitively and legitimately answer this question so we’re not comparing trial to trial, but actually looking head to head.

Benjamin H. Lowentritt, MD, FACS: That’s great. We always look forward to that. Understandably, you have companies that are bringing products to market; they’re not always looking to do projects like that, so it’s extremely important for us to be able to understand in any comparative way. It also sometimes feels like the studies underestimate what we see in our patients when we’re dealing with them outside of a clinical trial, because there’s so much support and guidance and investment from the patients.

In wanting to be a part of the trial, sometimes their attitude is a little different. In some of the metrics when it comes to fatigue and other indicators of quality of life, you wonder if patients aren’t giving a rosier picture because they want it to be a success. And that’s well described and part of every trial. But especially when the No. 1 adverse effects you’re seeing are things like fatigue, it’s reasonable to think that people might think it’s OK or not as critical to answer a question on a questionnaire that would say, “It’s worse.”

But it’s interesting. As we get the patient-reported outcomes, especially looking at some of the trials, the earlier trials with enzalutamide and apalutamide both seem to have pretty good patient-reported outcomes overall. So even though specific adverse effects may look one way or the other in these different trials, overall, patients are able to stay on the drug in most cases and express that they’re able to do most of their regular activities and have pretty good outcomes. We’re very fortunate to have multiple options in these disease states that we can feel we’re able to offer them. As you say, you get used to one, and you also have the option to switch them if you need to or dose adjust and all of that. We’re in a good place where we have all these different options.

Julie N. Graff, MD: May I add something, Ben?

Benjamin H. Lowentritt, MD, FACS: Please.

Julie N. Graff, MD: You’re making an excellent point. You can especially imagine that when a patient’s PSA [prostate-specific antigen] is coming down, he’s so happy that’s happening that he’s going to underreport these other issues. On the other side, patients on clinical trials are known to be healthier than patients out in the community. I wanted to share with you that I had the pleasure of doing an analysis of men ages 75 and older who were treated with enzalutamide for metastatic chemotherapy-naїve disease, so mCRPC [metastatic castration-resistant prostate cancer], but prior to docetaxel. The patients 75 and older on placebo had an 8% risk of fall, and those who got enzalutamide had a 20% risk. I was talking to my colleague who’s an exercise scientist and she said, “Oh my gosh, both of these numbers are underreported.” People 75 and older are falling like 30% of the time. So we’re not really good at capturing some of these end points.

Benjamin H. Lowentritt, MD, FACS: Right. It also came up in some of these trials where there was some thought that the way people were asking questions about adverse effects, or the intervals of adverse events were maybe different. You get to this point and you realize that, depending on how you ask the question, you’re going to get certain different answers. It’s always important to understand the data and look at it yourself and keep it in context for that specific treatment, and like you said, not compare too much across different trials.

Transcript edited for clarity.

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